The disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds. The compounds are ligands, agonists and partial agonists for the mGluR5 receptor and may be useful for the treatment of various disorders of the central nervous system.
Glutamate is the major excitatory neurotransmitter in the mammalian brain, playing an important physiological role in a wide variety of processes. Glutamatergic neurotransmission is predominantly mediated through activation of cell surface receptors including ligand-gated ion channels (ionotropic receptors) and metabotropic glutamate G protein coupled receptors (mGluRs). The metabotropic glutamate receptor family is comprised of 8 family members that are part of the family 3 GPCR superfamily. These receptors are further subdivided into Group I (mGluR 1, 5), Group II (mGluR 2, 3) and Group III (mGluR 4, 6, 7, 8) based upon sequence homology, receptor signaling, and pharmacology.
The Group I receptor mGluR5 has emerged as a target of potential therapeutic utility in a number of disease states (see: Rodriguez, A. L., et al. Current Opinion in Drug Discovery & Development (2007), 10(6), 715-722. and Chen, Y., et al. Drugs of the Future (2008), 33(4), 355-360. and Lindsley, C. W., et al. Current Opinion in Drug Discovery & Development (2009), 12(4), 446-457). The receptor is expressed broadly throughout the CNS with predominant post-synaptic localization, although pre-synaptic expression is also present. mGluR5 is a Gαq-coupled receptor activating phospholipase C and elevating intracellular calcium levels, leading to activation of downstream signaling molecules. Many studies have demonstrated a role for the receptor in regulating NMDA receptor activity as well as synaptic plasticity, suggesting this receptor plays a key role in glutamatergic signal transduction.
Based on the expression pattern and functional role of mGluR5, this receptor has emerged as an important target for drug discovery in a number of therapeutic indications. Evaluation of genetically modified mice lacking mGluR5 as well as compounds that modulate receptor function suggest ligands that modulate mGluR5 receptor function have therapeutic utility in CNS and peripheral disease states including, but not limited to, schizophrenia (see: Conn, P. J., et al. Trends in Pharmacological Sciences (2009), 30(1), 25-31; and Kanuma, K., et al. Recent Patents on CNS Drug Discovery (2010), 5(1), 23-34), cognitive impairment (see: Simonyi, A., et al. European Journal of Pharmacology (2010), 639(1-3), 17-25), Alzheimer's disease, Parkinson's disease (see: Johnson, K. A., et al. CNS & Neurological Disorders Drug Targets (2009), 8(6), 475-491), Parkinson's disease levodopa-induced dyskinesia (see: Rylander, D., et al. Neurobiology of Disease (2010), 39(3), 352-361), addiction (see: Olive, M. F. Current Drug Abuse Reviews (2009), 2(1), 83-98), anxiety (see: Jacob, W., et al. Neuropharmacology (2009), 57(2), 97-108), depression (see: Witkin, J. M., et al. CNS & Neurological Disorders: Drug Targets (2007), 6(2), 87-100), psychosis, epilepsy, Fragile X (see: Dolen, G., et al. Journal of Physiology (Oxford, United Kingdom) (2008), 586(6), 1503-1508), gastroesophageal reflux disease (see: Boeckxstaens, G. E. Expert Opinion on Emerging Drugs (2009), 14(3), 481-491), migraine (see: Marin, J., et al. Expert Opinion on Investigational Drugs (2010), 19(4), 555-561), pain, and others.
The invention provides technical advantages, for example, the compounds are novel and are ligands for the mGluR receptor and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.